AMP-activated protein kinase is essential for survival in chronic hypoxia

Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical School, Mayer Building 440, 44 Binney Street, Boston, MA 02115, USA.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 06/2008; 370(2):230-4. DOI: 10.1016/j.bbrc.2008.03.056
Source: PubMed


This study was undertaken to interrogate cancer cell survival during long-term hypoxic stress. Two systems with relevance to carcinogenesis were employed: Fully transformed BJ cells and a renal carcinoma cell line (786-0). The dynamic of AMPK activity was consistent with a prosurvival role during chronic hypoxia. This was further supported by the effects of AMPK agonists and antagonists (AICAR and compound C). Expression of a dominant-negative AMPK alpha resulted in a decreased ATP level and significantly compromised survival in hypoxia. Dose-dependent prosurvival effects of rapamycin were consistent with mTOR inhibition being a critical downstream mediator of AMPK in persistent low oxygen.

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    • "The role of AMPK in neuroprotection during metabolic stress, however, remains controversial. AMPK activation has been shown to be protective under stress conditions such as cryostorage [56], ischemia [57], chronic hypoxia [58], and glucose deprivation [59]. However, it has also been shown in vivo to be associated with increased tissue damage following ischemia [51], and inhibition of AMPK can be neuroprotective in some cases [53], [60]. "
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    ABSTRACT: Nervous systems are energetically expensive to operate and maintain. Both synaptic and action potential signalling require a significant investment to maintain ion homeostasis. We have investigated the tuning of neural performance following a brief period of anoxia in a well-characterized visual pathway in the locust, the LGMD/DCMD looming motion-sensitive circuit. We hypothesised that the energetic cost of signalling can be dynamically modified by cellular mechanisms in response to metabolic stress. We examined whether recovery from anoxia resulted in a decrease in excitability of the electrophysiological properties in the DCMD neuron. We further examined the effect of these modifications on behavioural output. We show that recovery from anoxia affects metabolic rate, flight steering behaviour, and action potential properties. The effects of anoxia on action potentials can be mimicked by activation of the AMPK metabolic pathway. We suggest this is evidence of a coordinated cellular mechanism to reduce neural energetic demand following an anoxic stress. Together, this represents a dynamically-regulated means to link the energetic demands of neural signaling with the environmental constraints faced by the whole animal.
    PLoS ONE 02/2014; 9(2):e88570. DOI:10.1371/journal.pone.0088570 · 3.23 Impact Factor
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    • "Although these strategies have clear impact on tumour growth and cellular proliferation, the current and previous data [18] [23] [24] indicate that caution should be taken in clinical regimens targeting these pathways as these drugs may promote tumour hypoxia. For example, the use of rapamycin in vitro increases hypoxia tolerance, whereas preventing decreased mTOR-signalling during hypoxia by AMPK-inhibitors leads to increased hypoxic cell killing [24]. Furthermore, administration of rapamycin to tumour bearing mice increased tumour hypoxia, and although a clear effect on tumour growth was seen, failed to improve response to fractionated radiotherapy [23]. "
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    Radiotherapy and Oncology 06/2011; 99(3):385-91. DOI:10.1016/j.radonc.2011.05.047 · 4.36 Impact Factor
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    ABSTRACT: Hypoxia is a consequence of inadequate oxygen availability. At the cellular level, lowered oxygen concentration activates signal cascades including numerous receptors, ion channels, second messengers, as well as several protein kinases and phosphatases. This, in turn, activates trans-factors like transcription factors, RNA-binding proteins and miRNAs, mediating an alteration in gene expression control. Each cell type has its unique constellation of oxygen sensors, couplers and effectors that determine the activation and predominance of several independent hypoxia-sensitive pathways. Hence, altered gene expression patterns in hypoxia result from a complex regulatory network with multiple divergences and convergences. Although hundreds of genes are activated by transcriptional control in hypoxia, metabolic rate depression, as a consequence of reduced ATP level, causes inhibition of mRNA translation. In a multi-phase response to hypoxia, global protein synthesis is suppressed, mainly by phosphorylation of eIF2-alpha by PERK and inhibition of mTOR, causing suppression of 5'-cap-dependent mRNA translation. Growing evidence suggests that mRNAs undergo sorting at stress granules, which determines the fate of mRNA as to whether being translated, stored, or degraded. Data indicate that translation is suppressed only at 'free' polysomes, but is active at subsets of membrane-bound ribosomes. The recruitment of specific mRNAs into subcellular compartments seems to be crucial for local mRNA translation in prolonged hypoxia. Furthermore, ribosomes themselves may play a significant role in targeting mRNAs for translation. This review summarizes the multiple facets of the cellular adaptation to hypoxia observed in mammals.
    Acta Physiologica 10/2008; 195(2):205-30. DOI:10.1111/j.1748-1716.2008.01894.x · 4.38 Impact Factor
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